Robust effect of metabolic syndrome on major metabolic pathways in the myocardium
| Autor: | Michael Sturek, Se Young Yoon, Maryam Karimi, Olivia Ziegler, Vahid Agbortoko, Jun Feng, Stoiana Alexandrova, Frank W. Sellke, Boian S. Alexandrov, Anny Usheva, Nivedita Sriram, Vasile I Pavlov, John M. Asara |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Metabolic Processes Glycogens Glycosylation Swine Glycobiology Gene Expression Biochemistry Cholesterol Dietary chemistry.chemical_compound 0302 clinical medicine Risk Factors Metabolites Medicine and Health Sciences Glycolysis Beta oxidation Metabolic Syndrome Mammals Multidisciplinary Glycogen Fatty Acids Eukaryota Heart Ketones Lipids beta-N-Acetylhexosaminidases Chemistry 030220 oncology & carcinogenesis Vertebrates Physical Sciences Ketone bodies Metabolome Medicine Anatomy Metabolic Networks and Pathways Research Article medicine.medical_specialty Science Pentose phosphate pathway N-Acetylglucosaminyltransferases 03 medical and health sciences Internal medicine medicine Genetics Animals Metabolomics RNA Messenger Catabolism Myocardium Organisms Chemical Compounds Biology and Life Sciences Metabolism Diet Metabolic pathway 030104 developmental biology Endocrinology chemistry Amniotes Cardiovascular Anatomy Acids Unsupervised Machine Learning |
| Zdroj: | PLoS ONE PLoS ONE, Vol 14, Iss 12, p e0225857 (2019) |
| ISSN: | 1932-6203 |
| Popis: | Although the high-fat-diet-induced metabolic syndrome (MetS) is a precursor of human cardiac pathology, the myocardial metabolic state in MetS is far from clear. The discrepancies in metabolite handling between human and small animal models and the difficulties inherent in obtaining human tissue complicate the identification of the myocardium-specific metabolic response in patients. Here we use the large animal model of swine that develops the hallmark criteria of human MetS. Our comparative metabolomics together with transcriptomics and computational nonnegative matrix factorization (NMF) interpretation of the data exposes significant decline in metabolites related to the fatty acid oxidation, glycolysis, and pentose phosphate pathway. Behind the reversal lies decreased expression of enzymes that operate in the pathways. We showed that diminished glycogen deposition is a metabolic signature of MetS in the pig myocardium. The depletion of glycogen arises from disbalance in expression of genes that break down and synthesize glycogen. We show robust acetoacetate accumulation and activated expression of key enzymes in ketone body formation, catabolism and transporters, suggesting a shift in fuel utilization in MetS. A contrasting enrichment in O-GlcNAcylated proteins uncovers hexosamine pathway and O-GlcNAcase (OGA) expression involvement in the myocardial response to MetS. Although the hexosamine biosynthetic pathway (HBP) activity and the availability of the UDP-GlcNAc substrate in the MetS myocardium is low, the level of O-GlcNacylated proteins is high as the O-GlcNacase is significantly diminished. Our data support the perception of transcriptionally driven myocardial alterations in expression of standard fatty acids, glucose metabolism, glycogen, and ketone body related enzymes and subsequent paucity of their metabolite products in MetS. This aberrant energy metabolism in the MetS myocardium provide insight into the pathogenesis of CVD in MetS. |
| Databáze: | OpenAIRE |
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